Overview

The goal of this clinical trial is to assess if BUCCALIN® works In the Prophylaxis of Recurrent Lower Respiratory Tract Infections (RLRTIS). It will also evaluate the safety of BUCCALIN®.

The primary aim is to reduce the number of infection episodes in the treatment period (12 months) in the BUCCALIN® group versus the Placebo group.

Patients diagnosed with RLRTIS will be screened for enrolment. Patients will be requested to provide informed consent before the start of the study related assessments.

Eligible patients who meet the study inclusion and exclusion criteria will be randomized with a 1:1 ratio allocation to the 2 treatment groups.

Researchers will compare BUCCALIN® (gastro-resistant tablets) to a placebo (gastro-resistant tablets containing only excipients) to treat RLRTIS.

Patients who participate in the study will perform several study visits divided as reported below:

• Run-in phase (12 months): patients will not receive any treatment. This phase is designed to increase adherence to the study and reduce loss to follow-up in the clinical trial. During this phase, patients should experience ≥ 2 episodes of RTIs to be eligible for the Treatment period.
• Treatment period (12 months): patients will receive BUCCALIN® or Placebo treatment for 12 consecutive months (3 days per month, posology as per authorized SmPC).
• Follow-up period (12 months): patients will not receive any treatment. This phase is designed to observe how patients respond to treatments.

Eligibility

Inclusion Criteria:

1. Patients willing and able to provide voluntary informed consent and to follow protocol requirements.
2. Male or females from 18 to 99 years old, (Adult, Older Adult).
3. Patients with Recurrent LRTIs including tracheitis, tracheobronchitis, acute bronchitis and exacerbations of chronic lung disease (asthma and/or COPD and/or bronchiectasis), who present with both of the following:
   1. ≥2 episodes within 12 months prior to the run-in period based on patient reported medical history (to access the run-in period) b) ≥2 episodes during the run-in period documented by appropriate microbiological diagnostic test (to access the treatment period)
4. Patients:
   1. not vaccinated or
   2. vaccinated against the most common pathogens for respiratory infectioan (within 12 months prior to the run-in period or during the run-in period, but not during the treatment period)\*:

      \- Anti-pertussis vaccination

      \- Covid-19 vaccination

      \- Respiratory Syncytial Virus vaccination

      \- Influenza vaccination

      \- Pneumococcal vaccination

      \* Patients vaccinated with other types of vaccines that have no effect on the lower respiratory tract (e.g. hepatitis b vaccination, shingles/herpes zoster vaccination, papilloma virus vaccine), in addition to the ones listed above, may also be included.

Exclusion Criteria:

RUN-IN period

1. Female patient: pregnant, lactating or planning pregnancy (Female of child-bearing potential will undergo urine pregnancy test).
2. Female of potential child-bearing that does not use at least one effective contraceptive method for the entire study.
3. Contraindication or known hypersensitivity to the active ingredients of bacterial lysates or any excipients listed in the ingredients.
4. Pneumonia (based on the EMA Referral Procedure EMEA/H/A-31/1465).
5. Known history of tuberculosis and/or cystic fibrosis.
6. Known history of immunodeficiency diseases (e.g., HIV infection, AIDS, or any type of congenital or iatrogenic immune deficiency, including IgA deficiency).
7. Severe heart failure (NYHA class III and IV).
8. Haematologic diseases including severe anaemia (defined according to the National Cancer Institute as Hemoglobin \< 8.0 g/dL).
9. Renal failure (eGFR \< 30 mL/min).
10. History of known liver damages defined by the METAVIR classification (F1-F4)\.
11. Malignancies with a remission period of \< 5 years.
12. Wheezing documented to be caused by gastroesophageal reflux\\*.
13. Patient legally or mentally incapacitated unable to give informed consent for the participation in this study.
14. Patient who is unable or unwilling to comply with the appointments or with all the requirements of the Protocol.
15. History of autoimmune diseases and acute intestinal infections, as reported in Buccalin® SmPC.
    • This criterion only applies to patients with known liver disease who can produce valid fibroscan and/or biopsy results and bring them for demonstration.
      • The criterion can only be applied if the patient presents clinically reliable documentation that the wheezing is not due to a lung disease (i.e. gastroscopy).

TREATMENT period

1. Female patient: pregnant, lactating or planning pregnancy (Female of child-bearing potential will undergo urine pregnancy test).
2. Female of potential child-bearing that does not use at least one effective contraceptive method for the entire study.
3. Contraindication or known hypersensitivity to the active ingredients of bacterial lysates or any excipients listed in the ingredients.
4. Pneumonia (based on the EMA Referral Procedure EMEA/H/A-31/1465).
5. Known history of tuberculosis and/or cystic fibrosis.
6. Known history of immunodeficiency diseases (e.g., HIV infection, AIDS, or any type of congenital or iatrogenic immune deficiency, including IgA deficiency).
7. Severe heart failure (NYHA class III and IV).
8. Haematologic diseases including severe anaemia (defined according to the National Cancer Institute Hemoglobin \< 8.0 g/dL).
9. Renal failure (eGFR \< 30 mL/min).
10. History of known liver damages defined by the METAVIR classification (F1-F4)\.
11. Malignancies with a remission period of \< 5 years.
12. Injection or oral administration of steroids within 4 weeks prior to randomization\\.
13. Use of immunosuppressants, immunostimulants, or gamma globulins within 6 months prior to randomization.
14. Previous use within 6 months prior to randomization or ongoing use of bacterial lysates.
15. Any major surgery within the last 3 months prior to randomization.
16. Wheezing documented to be caused by gastroesophageal reflux\\*\*.
17. Patient legally or mentally incapacitated unable to give informed consent for the participation in this study.
18. Patient who is unable or unwilling to comply with the appointments or with all the requirements of the Protocol.
19. History of autoimmune diseases and acute intestinal infections, as reported in Buccalin® SmPC.
    • This criterion only applies to patients with known liver disease who can produce valid fibroscan and/or biopsy results and bring them for demonstration.
      • In these instances, patients may undergo a washout period of 4 weeks to qualify for the treatment period.
        • The criterion can only be applied if the patient presents clinically reliable documentation that the wheezing is not due to a lung disease (i.e. gastroscopy).